Electrophilic Aromatic Nitration: Understanding Its Mechanism

and Substituent Effects

Jorge Freire de Queiroz, Jose Walkimar de M. Carneiro,*, Adao A. Sabino,
Regina Sparrapan, Marcos N. Eberlin,*, and Pierre M. Esteves*,|
Instituto de Qumica, UniVersidade Federal Fluminense, Outeiro de Sa o Joa o Batista, s/n, 24020-150,
Nitero i-RJ, Brazil, Instituto de Qumica, UniVersidade Estadual de Campinas, Laborato rio ThoMSon de
Espectrometria de Massas, Campinas, SP, Brazil, and Instituto de Qumica, UniVersidade Federal do Rio
de Janeiro, Cidade UniVersita ria, CT Bloco A, 21949-900, Rio de Janeiro-RJ, Brazil
walk@kabir.gqt.uff.br; eberlin@iqm.unicamp.br; pesteVes@iq.ufrj.br
ReceiVed May 7, 2006

Theoretical calculations and gas-phase mass spectrometric studies were performed for the reaction of the
naked (NO2+) and monosolvated (CH3NO2NO2+) nitronium ion with several monosubstituted aromatic
compounds. From these studies, we propose a general model for regioselectivity based on the singleelectron transfer (SET) mechanism and an alternative mechanistic scheme for electrophilic aromatic
nitration. This scheme considers the SET and the polar (Ingold-Hughes) mechanisms as extremes in a
continuum pathway, the occurrence and extents of both mechanisms being governed mainly by the ability,
or lack of ability, of the aromatic compound to transfer an electron to NO2+.

Introduction
The mechanism of electrophilic aromatic nitration has been
enthusiastically debated over decades.1-8 Ingold and Hughes
considered the nitronium ion (NO2+) as the reactive electrophile
This manuscript is dedicated to Prof. W. B. Kover for his outstanding work
on reaction mechanisms.
Universidade Federal Fluminense.
Universidade Estadual de Campinas.
| Universidade Federal do Rio de Janeiro.

(1) (a) Hughes, E. D.; Ingold, C. K.; Reed, R. I. Nature 1946, 158, 448.
(b) Ingold, C. K.; Hughes, E. D. et al.; J. Chem. Soc. 1950, 2400. (c) Ingold,
C. K. Structure and Mechanism in Organic Chemistry; Cornell University
Press: New York, 1969.
(2) (a) Wheland, G. W.; J. Am. Chem. Soc. 1942, 64, 900. (b) Wheland,
G. W. The Theory of Resonance; Wiley: New York, 1944. (c) Olah, G. A.
Acc. Chem. Res. 1971, 4, 240.
(3) Melander, L.; Isotope Effects on Reaction Rates; Ronald Press: New
York, 1960.
(4) (a) Kenner, J. Nature, 1945, 156, 369. (b) Weiss, J. Trans. Faraday
Soc. 1946, 42, 116.
(5) Perrin, C. L. J. Am. Chem. Soc. 1977, 99, 5516.

that attacks the aromatic compound (ArX) to form an ArXNO2+

intermediate.1 This key intermediate is frequently referred to
as the Wheland intermediate, complex, or arenium ion.2
Subsequently, ArXNO2+ eliminates H+, and the neutral nitrated
product is formed.3 This classical interpretation is known as
the Ingold-Hughes or polar two-electron mechanism of electrophilic aromatic nitration. Kerner and Weiss also offered an
alternative mechanism that assumes single-electron transfer
(SET) from the aromatic substrate to NO2+.4 Pair recombination
of the two nascent SET products (the aromatic radical cation
ArH+ and the NO2 radical) would then afford the same
Ingold-Hughes arenium ion intermediate ArHNO2+ (Scheme
1).
(6) Eberson, L.; Hartshorn, M. P.; Radner, F. Acta Chem. Scand. 1994,
48, 937.
(7) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration Methods and
Mechanism; VCH: New York, 1989.
(8) Kochi, J. K. Acc. Chem. Res. 1992, 25, 39.
10.1021/jo0609475 CCC: $33.50 2006 American Chemical Society

6192

J. Org. Chem. 2006, 71, 6192-6203

Published on Web 06/30/2006

Electrophilic Aromatic Nitration

FIGURE 1. Key SET intermediates found by DFT calculations for nitration of benzene.
SCHEME 1

Although the Ingold-Hughes mechanism has prevailed, the

SET mechanism has attracted renewed attention. A turning point
occurred in 1977 when Perrin5 showed that electrochemical
nitration of naphthalene yields the same proportion of products
as that obtained on usual acidic nitration. Although Perrins
results were at first contested,6 they raised a vivid dispute on
the validity and limits of the two mechanistic proposals.7 Kochi
and co-workers8 offered considerable advance in clarifying the
dispute by providing strong evidence for the SET mechanism
based mainly on experimental results. They also formulated a
slightly different SET mechanism in which more intermediates
are involved. Nowadays, the SET mechanism seems to be firmly
supported on an experimental base, particularly for the more
activated (electron-rich) aromatics, hence coexisting on equal
grounds (and therefore mixing up) with the Ingold-Hughes
mechanism.
The first theoretical investigations reported on SET mechanism for electrophilic aromatic nitration were also controversial.9
However, high level theoretical investigations have corroborated
the experimental findings pointing firmly to the SET mechanism.10 Recently, we11 employed B3LYP/6-311++G(d,p) cal(9) (a) Politzer, P.; Jayasuriya, K.; Sjoberg, P.; Laurence, P. R.; J. Am.
Chem. Soc. 1985, 107, 1174. (b) Feng, J.; Zheng, Z.; Zerner, M. C.; J.
Org. Chem. 1986, 51, 4531. (c) Gleghorn, J. T.; Torossian, G. J. Chem.
Soc., Perkin Trans. 2 1987, 1303.
(10) (a) Peluso, A.; Del Re, G.; J. Phys. Chem. 1996, 100, 5303. (b)
Albunia, A. R.; Borrelli, R.; Peluso, A. Theor. Chem. Acc. 2000, 104, 218.
(11) Esteves, P. M.; Carneiro, J. W. d. M.; Cardoso, S. P.; Barbosa, A.
G. H.; Laali, K. K.; Rasul, G.; Prakash, G. K. S.; Olah, G. A. J. Am. Chem.
Soc. 2003, 125, 4836.

culations to show that gas-phase nitration of benzene with NO2+

involves first an electrostatically bonded complex, which is
better described as a charge-transfer complex (Figure 1), in
which NO2+ interacts with the whole aromatic system of
benzene through one of its oxygen atoms. SET occurs within
this initial complex thus yielding a second complex, that is,
a SET-intimate ion pair, which further collapses to the
complex. Theoretical calculations12 by other groups have also
supported this model.
The proposal of a first complex as an intermediate allowed
us to rationalize some intriguing experimental findings from
gas-phase ion/molecule reactions13 and in the condensed phase.14
For instance, it has been observed that, instead of the addition
of NO2+ to benzene, the ion/molecule reaction between gaseous
NO2+ and benzene occurs by oxygen atom transfer (formally
O+) to form C6H6O+.15 On the basis of the SET mechanism,
we have shown11 that a phenol radical cation complexed to NO
is the lowest energy species on the overall potential energy
surface of C6H6NO2+. The loss of NO by this complex is the
preferred pathway, affording the phenol radical cation (C6H6O+).
(12) (a) Gwaltney, S. R.; Rosokha, S. V.; Head-Gordon, M.; Kochi, J.
K. J. Am. Chem. Soc. 2003, 125, 3273. (b) Chen, L.; Xiao, H.; Xiao, J.;
Gong, X. J. Phys. Chem. A 2003, 107, 11440.
(13) (a) Attina`, M.; Cacace, F.; Yanez, M. J. Am. Chem. Soc., 1987,
109, 5092. (b) Aschi, M.; Attina`, M.; Cacace, F.; Ricci, A. J. Am. Chem.
Soc. 1994, 116, 9535. (c) Attina`, M.; Cacace, F.; de Petris, G. Angew. Chem.,
Int. Ed. Engl. 1987, 26, 1177. (d) Cacace, F. Acc. Chem. Res. 1988, 21,
215.
(14) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration Methods and
Mechanism; VCH: New York, 1989; Chapter 3.

J. Org. Chem, Vol. 71, No. 16, 2006 6193

Queiroz et al.
TABLE 1. B3LYP/6-311++G(d,p)//B3LYP/6-31++G(d,p) Relative Energies in Kcal Mol-1 for the Minima Found for Species 1-4 (Scheme 2)
Proposed for the Reaction of Gaseous NO2+ with Selected Monosubstituted Aromatic Compounds via the SET Mechanisma
X
species

NO2

CHO

CF3

CN

CH3

Cl

Br

OH

1
2a
2b
2c
2d
3a
3b
3c
3d
4

1f4
17.3
15.4
15.7
16.8
3a f 2a
3b f 2b
17.7
18.7
0.0

12.0c
2a f 2b
18.8
18.0
18.5
-17.6b
20.6
18.0
19.0
0.0

7.6d
2.5
0.0
0.5
1.4
8.1
3b f 2b
1.5
2.6
5.6

20.3
12.0
11.2
12.3
10.7
3a f 2a
13.2
14.5
11.7
0.0

14.3f
0.7f

3.0e
4.3
4.2
6.7
2d f 3d
8.4
2.4
5.8
0.0

-3.4c
3.4
4.4
2c f 2d
1.3
3a f 2a
4.5
8.4
0.0
12.1

-2.7c
3.4
4.1
2c f 2d
1.6
3a f 2a
3.9
8.3
0.0
6.3

-3.5c
4.0
3.5
2c f 3d
1.4
11.1
3.8
8.5
0.0
2.9

-2.4c
8.0
2b f 3b
2c f 3d
2d f 3d
3a f 2a
4.8
16.8
0.0
15.3

0.0f

a The blank fields mean that the structures could not be found as minima on the potential energy surface after geometry optimization. b 3a rearranges to
PhNO2H+CO upon geometry optimization. c Oxygen transfer to the ortho position. d Bent over the substituent, oxygen pointing toward ipso position
e Oxygen transfer to the ipso position f From ref 11.

The reaction of the radical cation of several aromatics with NO2

has been studied.16 The complex was readily formed for
activated aromatics, whereas aromatics highly deactivated by
multiple fluorine substitution were found to be nonreactive at
all. Comparing these results with the lack of adduct formation
in the reaction of aromatics with NO2+ (as we show here
however, monosolvated NO2+ does add to aromatics), it was
concluded that the ionized aromatic is a plausible intermediate
in aromatic nitration. Speranza and co-workers17 used ICR
experiments to show that SET is faster than ring nitration in
the reaction of (RONO2)H+ with aromatics, which eventually
reacts with the precursor RONO2 to afford oxygen transfer and
nitration products. They also have shown that the direct oxygen
and NO2 group transfers from (RONO2)H+ to the aromatic
compound are slower than the single electron transfer. Therefore
these experimental results,15-17 when analyzed in view of the
SET mechanism,11 are easily understood.
In an ongoing investigation aimed to fully understand the
mechanism of electrophilic aromatic nitration, we report herein
the results from a systematic experimental and theoretical study
of the reaction of gaseous NO2+ with monosubstituted aromatic
compounds. These results are evaluated in view of substituent
effects and considering both the SET and the Ingold-Hughes
mechanism for electrophilic nitration reactions. From these
studies, we propose a model for regioselectivity based on the
SET mechanism and a general mechanistic scheme for electrophilic aromatic nitration conciliating, for the first time, the
two coexisting views.
Results and Discussions
Theoretical Calculations on Key SET Species. The reaction
of NO2+ with selected aromatic compounds was initially studied
by DFT using the B3LYP hybrid functional and the 6-311++G(d,p) basis set (6-31++G(d,p) for geometry optimization).18
Many possible orientations for the approximation of NO2+ to
(15) (a) Benezra, S. A.; Hoffman, M. K.; Bursey, M. M. J. Am. Chem.
Soc. 1970, 92, 7501. (b) Hoffman, M. K.; Bursey, M. M. Tetrahedron Lett.
1971, 2539. See also (c) Dunbar, R. C.; Shen, J.; Olah, G. A. J. Am. Chem.
Soc. 1972, 94, 6862. (d) Ausloos, P.; Lias, S. G. Int. J. Chem. Kinet. 1978,
10, 657. (e) Morrison, J. D.; Stanney, K.; Tedder, J. M. J. Chem. Soc.,
Perkin Trans. 2 1981, 967.
(16) (a) Schmitt, R. J.; Ross, D. S.; Buttrill, S. E. J. Am. Chem. Soc.
1981, 103, 5265. (b) Schmitt, R. J.; Buttrill, S. E.; Ross, D. S. J. Am. Chem.
Soc. 1984, 106, 926.
(17) Attina`, M.; Cacace, F.; Speranza, M. Int. J. Mass Spectrom. Ion
Processes 1992, 117, 37.

6194 J. Org. Chem., Vol. 71, No. 16, 2006

SCHEME 2

the aromatic compounds were considered (Scheme 2). See

computational details for additional information.
Table 1 summarizes the relative energies for the main
intermediates found on the potential energy surface for the
interaction of NO2+ with C6H5X (Scheme 2). Information on
selected geometrical parameter and absolute energies, zero-point
vibrational energy (ZPE), and thermal corrections to 298.15 K
and 1 atm are provided as Supporting Information.
The potential energy surface for addition of NO2+ to benzene
is rather complex.11 When unsymmetrical aromatic systems are
considered, this complexity becomes even greater as compared
to the symmetric benzene molecule. A wide set of minimum
energy structures may be located, from which at least three are
of primary relevance to the nitration mechanism. The first
minimum is a weak complex that represents a preorganized
weakly bonded state, where low energy, nonspecific, and
(18) (a) Hohenberg, P.; Kohn, W. Phys. ReV. 1964, 136, B864. (b) Kohn,
W.; Sham, L. J. Phys. ReV. 1965, 140, A1133. (c) Parr, R. G.; Yang, W.
Density-Functional Theory of Atoms and Molecules; Oxford University
Press: Oxford, U.K. 1989.

Electrophilic Aromatic Nitration

attractive interaction between NO2+ and the aromatic system

as a whole occurs. This initial complex is followed by SET
from the aromatic ring to NO2+, resulting in an intimate ionpair intermediate where a bent NO2 molecule interacts with the
benzene radical cation.11 Collapse of the last intermediate affords
the classical Wheland intermediate ( complex).
Ring substituents should have therefore strong effects on the
relative stability of the relevant intermediates. A major substituent effect is on the energy and structure of the unoriented
complex. For benzene (the parent aromatic compound), NO2+
is found to lay in the axis normal to the molecular plane of the
aromatic ring with a stabilization energy of -9.2 kcal mol-1.11
Similar arrangements were located only for the aromatics
bearing the electron-withdrawing deactivating substituents CN
and CF3. These substituents are known to decrease nitration rate,
as compared to benzene, and direct nitration to the meta position.
Additionally, for the NO2, CHO, CN, and CF3 substituents, SET
is endothermic11 (vide Supporting Information, Table S10). For
activating substituents (F, CH3, OH), SET is exothermic and
the first complex intermediate could not be located. During
geometry optimization, even when using an input geometry that
forced NO2+ into a linear arrangement lying in the same axis
as that of the aromatic ring, the structure converges directly to
the SET intimate ion-pair complex. Therefore, the SET energetics seems to represent the main parameter that determines
whether the complex will be formed, whereas benzene
represents the borderline for the process. Deactivating substituents leads to endergonic SET, therefore forming the complex.
In contrast, for activated substituents with exorgonic SET, this
complex could not be located.
The geometry of the complex for benzonitrile (X ) CN)
is similar to that calculated for benzene. In this complex, NO2+
places itself in an axis perpendicular to the molecular plane of
the aromatic ring. The only uncommon structure is found for
trifluoro-toluene, that is, when the benzene ring bears the highly
electronegative substituent CF3. NO2+ is found to move toward
the substituent, and in the optimized structure it is located quite
near to the CF3 group, possibly owing to a strong electrostatic
interaction.
The complex just discussed may be considered as a chargetransfer complex involving electrostatic interactions. Analysis
of CHelpG charges on the NO2 and on the ArX moieties shows
that these complexes have most of the positive charge on the
NO2 group, corroborating its description as a complex. From
this initial complex, the reaction evolves to the intimate ionpair complex, where a bent NO2 interacts with the aromatic
ring. Therefore, the clear-cut step is SET from the aromatic ring
to NO2+, either via the unoriented preorganized complex or
via a direct electron shift for those cases where SET is
exorgonic.
Table 1 shows that all deactivated compounds with metadirecting substituents (X ) NO2, CHO, CF3, CN) have structures
of the type 2b and 2c; that is, complexes at ortho and meta
positions are the most stable ones. This trend seems to be general
for this series. SET is also endorgonic in this series, in agreement
with estimates from differences in experimental ionization
energies (IE).11 Conversely, activated aromatic compounds
containing ortho/para directing substituents form complexes
(3) that are more stable than 1 or 2. Analysis of charge densities
for 2 shows that its positive charge is located mainly on the
aromatic ring, indicating that SET to NO2+ has already occurred.

Thus, 2 is constituted formally of a pair of the NO2 radical

and the radical cation of the aromatic molecule ArX+.
Therefore, structures 2 are better described as SET intimate
pairs, as observed for the nitration of benzene.11
Halogen-substituted aromatics are interesting substrates for
nitration since they are deactivated (as compared to benzene),
but substitution is directed to the ortho and para positions.19
Therefore halobenzenes behave as borderlines. The present
calculations show that they behave similarly to the activated
aromatics, once they present exothermic SET.
Gas-Phase Reactions of NO2+. To gain further insight as to
whether and when SET or Ingold-Hughes mechanism operates,
we performed mass spectrometric experiments in which gasphase reactions of the isolated NO2+ and some selected
aromatics were investigated. A pentaquadrupole mass spectrometer (Q1q2Q3q4Q5) was used.20 First, we have reacted
naked NO2+ generated by 70 eV electron ionization (EI) of
nitro-methane (CH3NO2). The ion was mass-selected by the first
quadrupole filter (Q1) and then sent to react with the aromatic
compound to the second quadrupole collision chamber (q4). The
product ion mass spectrum was then recorded by scanning the
third quadrupole filter (Q5). As the spectrum of Figure 2
exemplifies for benzene, naked NO2+ reacts with the aromatics
predominantly by electron abstraction yielding exclusively
ionized benzene of m/z 78. None of the expected adduct of m/z
124 (likely the Wheland intermediate) was observed. Probably
because direct addition of NO2+ to benzene is strongly
exothermic, the nascent product is too hot to survive when it is
isolated in the gas phase. The minor product ion of m/z 66
indicates that oxygen atom transfer also occurs to form hot
ionized phenol, which dissociates readily by CO loss to the
C5H6+ ion of m/z 66. CO loss is the major dissociation observed
for ionized phenol under EI, and the C5H6+ ion has been
rationalized as the cyclopentadienyl cation formed via the
cyclohexadienone intermediate.21 The formation of a C6D6O+
product ion of m/z 100 (likely ionized phenol) in reactions of
NO2+ with benzene-d6 has been reported.15
To quench the ion/molecule products and hence to reduce or
suppress their reaction-induced dissociation, we performed
the next reactions with a monosolvated NO2+ ion. As observed
before for other monosolvated ions,22 the third body (solvent)
removes part of the energy released in the course of the reaction
thus favoring the observation of the intact adduct of NO2+ with
aromatics and olefins. Self-chemical ionization (CI) of CH3NO2 was then used to form CH3NO2NO2+ of m/z 107.23
Figure 3a shows the spectrum for the gas-phase reactions of
CH3NO2NO2+ of m/z 107 with benzene. Now for the monosolvated ion, three major products are formed. The adduct with
benzene of m/z 124 is clearly detected. The product ion of m/z
(19) March, J. AdVanced Organic Chemistry; John Wiley & Sons: New
York, 1985.
(20) Eberlin, M. N. Mass Spectrom. ReV. 1997, 16, 113.
(21) Beynon, J. H.; Lester, G. R.; Williams, A. E. J. Chem. Phys. 1959,
63, 1861.
(22) (a) Dunbar, R. C.; Shen, J.; Olah, G. A. J. Am. Chem. Soc. 1972,
94, 6862. (b) Cacace, F.; Attina`, M.; de Petris, G.; Speranza, M. J. Am.
Chem. Soc. 1994, 116, 6413. (c) Meurer, E. C.; Cabrini, L. G. ; Gozzo, F.
C.; Eberlin, M. N. J. Mass Spectrom. 2006, 41, 735-740.
(23) Higher degree of solvation of NO2+ by CH3NO2 was not observed,
despite many attempts to increase pressure and reduce the kinetic energy
of the ions inside the CI cell. This limitation is probably because of the
way the NO2+ is solvated (see text), which obstructs a second CH3NO2
molecule to strongly interact with NO2+.

J. Org. Chem, Vol. 71, No. 16, 2006 6195

Queiroz et al.

FIGURE 2. Product ion mass spectrum for the gas-phase reaction of naked NO2+ of m/z 46 with benzene (78 Da).

FIGURE 3. (a) Product ion mass spectrum for the gas-phase reaction of CH3NO2NO2+ of m/z 107 with benzene (78 Da). (b) Sequential product
ion mass spectrum for 15 eV CID of the adduct of benzene and NO2+ of m/z 124.

94 is attributed to ionized phenol formed by oxygen atom (O+)

transfer, that is, by NO loss from the intact adduct. The ion of
m/z 78 is ionized benzene that can be accounted to be formed
by SET if we consider that the gaseous intimate SET complex
6196 J. Org. Chem., Vol. 71, No. 16, 2006

is too hot and too weakly bonded to survive (no substantial

heat removal from solvent) thus dissociating to ionized benzene
and NO2 before collapsing to the Wheland intermediate (the
adduct).

Electrophilic Aromatic Nitration

SCHEME 3

Figure 3b shows the sequential product ion mass spectrum

for the adduct of benzene with NO2+, that is PhHNO2+. The
dissociation chemistry observed can be rationalized in terms of
a mixture of coexisting or interconverting isomers (Scheme 3).
The fragment of m/z 94 (likely ionized phenol formed by O+.
transfer)14 indicates dissociation of a species covalently bonded
through the oxygen. The fragment of m/z 78 may be rationalized
in terms of the Wheland intermediate that dissociates via the
intermediacy of the intimate PhH+/NO2 SET complex (Figure
1). The fragment of m/z 78 (ionized benzene, PhH+) may then
dissociate further by H loss to form Ph+ of m/z 77, but this
fragment may also be formed from the Wheland intermediate
after proton shift.
Figure 4 shows now the spectra for the gas-phase reactions
of CH3NO2NO2+ with toluene and anisole. If we consider the
Ingold-Hughes mechanism, the increase of the nucleophilicity
of the aromatic ring, as for toluene and anisole, would be
expected to favor adduct formation. The SET mechanism would
otherwise predict higher tendency of these electron-rich rings
to transfer an electron to NO2+. Lower yields for the PhXNO2+
adducts and higher yields of the ionized aromatics are observed,
as compared to benzene (Figure 3a), and therefore these results
are fully in line with the SET mechanism for nitration of
aromatics.11 In fact, anisole (Figure 4b) forms no PhOCH3NO2+
adduct at all, and ionized anisole of m/z 108 dominates.
In great contrast to benzene and the activated aromatics
(toluene and anisole), CH3NO2NO2+ reacts with the deactivated
aromatic nitrobenzene forming the adduct PhNO2NO2+ exclusively, with electron transfer (PhNO2+ of m/z 123) being
entirely suppressed (Figure 5).
This contrasting behavior for activated and deactivated
aromatics, for instance anisole (Figure 4b) and nitrobenzene
(Figure 5), is therefore in opposition with the Ingold-Hughes
mechanism, whereas it is fully consistent with the SET
mechanism. The lower IE of the activated aromatics favor
electron transfer (SET) as opposed to adduct formation, whereas
the higher IE of nitrobenzene hampers electron-transfer thus
favoring direct eletrophilic attack with adduct formation (see
Table S10, in the Supporting Information, for details).
Another tough test for the SET mechanism is offered by the
reactions of CH3NO2NO2+ with the halobenzenes. In eletrophilic aromatic substitution, the halogens Cl, Br, and I deactivate
the aromatic ring but direct attack to the ortho/para positions.
This classical dichotomy in aromatic substitution reactions has
been explained by an imbalance between resonance (ortho/para
orientation) and inductive effects (lower reactivity as compared
to benzene).19
In full accordance with the SET mechanism, CH3NO2NO2+
reacts with the halobenzenes mainly by electron abstraction
(Figure 6), whereas the lower the ionization energies (F > Cl

> Br > I)11, the higher the yield of the ionized halobenzene as
compared to that for the PhXNO2+ adduct. In fact, only
fluorobenzene and chlorobenzene form detectable amounts of
PhXNO2+ as well as the corresponding ionized halophenols,24
whereas bromobenzene and iodobenzene afford only PhX+,
probably as the result of their lowest IE within the halogen series
(Table S10).
The key question that now rises is How can we predict how
readily an aromatic ring can transfer a single electron to NO2+?
The low feasibility of such process has been a main argument
against the generalization of the SET mechanism for electrophilic aromatic nitration. This question may be addressed by
inspection of the IE of the aromatics. Experimental IE measured
in the gas phase are available25 and provide an indication for
the thermodynamic feasibility of the SET process.11
SET to NO2+ from the parent aromatic compound benzene
(-7.89 kcal mol-1) as well as from the activated aromatics
toluene (-17.48 kcal mol-1), phenol (-25.27 kcal mol-1),
anisole (-31.96 kcal mol-1), and aniline (-43.03 kcal mol-1)
is thermodynamically favored (see table S10, for selected
values). This favoring therefore increases as a function of the
electron donating ability of the substituent.11 SET for the
deactivated and meta-orientating substituted aromatics nitrobenzene (+8.16 kcal mol-1), trifluorotoluene (+2.28 kcal mol-1),
and benzonitrile (+3.32 kcal mol-1) are, as expected, unfavorable. Nevertheless, and again as observed experimentally, the
deactivated and ortho/para orientating halobenzenes are predicted to undergo exothermic SET to NO2+ (IE < 0), in the
order: F (-8.90 kcal mol-1) > Cl (-11.9 kcal mol-1 > Br
(-13.5 kcal mol-1) > I (-20.0 kcal mol-1). The SET
mechanism can also explain the observed ortho/para selectivity
in the electrophilic nitration of halobenzenes, an unusual
orientation for such deactivating groups (Figure 9, see infra).
Care should be taken, however, to use gas-phase IE since they
provide only a rough prediction for solution behavior. This is
so because solvent and counterion effects can change intrinsic
IE, especially for the small NO2+. Therefore, large gas-phase
IE are unlikely to be inverted by solution effects but inversions
for small IE may occur. If so, depending on the solvent and
counterion, or both, nitration may follow either the SET or
Ingold-Hughes mechanism, and a general model accounting
for this behavior is discussed below. The SET mechanism can
therefore be more evident in some solvents, especially in polar
aprotic ones (Figure 7).
In aprotic polar media, such as nitromethane, the solvation
of NO2+ is basically nucleophilic. Thus, its solvation occurs
mainly at the positively charged nitrogen atom, which makes
the N site less accessible for nucleophilic attack. This trend was
observed in our gas-phase experiments, since NO2+ was unable
to be monosolvated for more than one nitromethane molecule.
The only related species observed in the self-ionization of CH3NO2 is the singly monosolvated NO2+ (CH3NO2NO2+ of m/z
107), despite all attempts to generate multisolvated species. If
SET occurs in this scenario, the charges on the system change.
On the NO2, now neutral because of SET, oxygen atoms bear
the negative charge, whereas the nitrogen atom tends to be
(24) The product ion mass spectrum for CID of ionized fluorophenol of
m/z 112 shows it dissociates mainly by CO loss.
(25) Linstrom P. J., Mallard, W. G., Eds. NIST Chemistry WebBook;
NIST Standard Reference Database Number 69, March 2003; National
Institute of Standards and Technology: Gaithersburg, MD, http://webbook.nist.gov. (See Supporting Information (Table S10) for summarized
data from NIST.)

J. Org. Chem, Vol. 71, No. 16, 2006 6197

Queiroz et al.

FIGURE 4. Product ion mass spectrum for the gas-phase reaction of CH3NO2NO2+ of m/z 107 with (a) toluene (92 Da) and (b) anisole (108 Da).

FIGURE 5. Product ion mass spectrum for the gas-phase reaction of CH3NO2NO2+ of m/z 107 with nitrobenzene (123 Da).

neutral to positive. However, the aromatic is now a radical

cation. There is greater tendency for an attack from the
negatively charged oxygen atoms to the ring, leading to oxygen
transfer products. This tendency explains the greater feasibility
6198 J. Org. Chem., Vol. 71, No. 16, 2006

of oxygen transfer in this case. Other reaction pathways are the

coupling through the nitrogen atom, leading to the N-bonded
Wheland intermediate, which will eventually afford the nitrated
product. However, this pathway requires NO2 rotation in the

Electrophilic Aromatic Nitration

FIGURE 7. Mechanistic scheme proposed for the nitration of aromatics

in aprotic (top) and protic (bottom) polar solvent. The asterisk sign (*)
on a species means that it is vibrationally and translationally excited.

FIGURE 6. Product ion mass spectrum for the gas-phase reaction of

CH3NO2NO2+ of m/z 107 with (a) fluorobenzene (96 Da), (b)

chlorobenzene (112/114 Da), bromobenzene (156/158 Da), and (d)
iodobenzene (204 Da).

SET intimate pair, which can also dissociate into NO2 and the
radical cation of the aromatic compound that could afford
products from radical processes.
However, if polar protic solvents are considered, the solvation
of NO2+ is both electrophilic and nucleophilic, respectively on
the oxygen and nitrogen atoms. Upon SET, the partially
negatively charged oxygen atoms on neutral NO2 are even more

strongly solvated by hydrogen bonds from the media, whereas

the nitrogen atom (in a radical) is relatively free of solvation
for coupling with the radical cation of the aromatic compound.
Thus, performing the reaction in polar protic or aprotic solvents
can lead to different products and behavior, which could be the
source for disagreement for the reaction mechanism.
A Frontier Molecular Orbital Model for SET. Analysis
of the frontier molecular orbitals in terms of the donor-acceptor
mechanism may help rationalize the role of the substituent on
the reaction rate and regioselectivity observed in solution. The
main interaction involves the highest occupied molecular orbital
(HOMO) of the donor species, the aromatic compound in the
present case, and the lowest unoccupied molecular orbital
(LUMO) of the acceptor: NO2+. Therefore, we need to
understand how the substituent affects the orbital energies of
the aromatic system. Figure 8 shows a pictorial representation
on the effect of substituents on the HOMO energies of the
aromatic compound. Benzene has two degenerate HOMO
orbitals, one of which is symmetric through mirroring whereas
the other one is antisymmetric. Upon substitution by an electron
donor substituent, Z, the degeneracy breaks down and the
symmetric orbital became the higher energy (HOMO), because
of the electron-electron repulsion of the electrons in the Z group
with the aromatic system. Conversely, upon substitution by
an electron withdrawing group, Y, the symmetric orbital is
stabilized, breaking down the degeneracy and leading the
antisymmetric orbital to be the HOMO in this case.26
(26) Fukuzumi, S.; Kochi, J. K.; J. Am. Chem. Soc. 1981, 103, 7240.

J. Org. Chem, Vol. 71, No. 16, 2006 6199

Queiroz et al.
TABLE 2. MP2(fc)/6-31G(d)//MP2(fc)/6-31G(d) Energies of

HOMO, HOMO - 1, LUMO and LUMO + 1 Orbitals in Hartrees

for the Selected Aromatic Compounds as Well as for NO2+
substrate

HOMO

HOMO - 1

LUMO

benzene
toluene
aniline
phenol
fluorbenzene
clorobenzene
bromobenzene
nitrobenzene
benzaldehyde
trifluormethylbenzene
NO2+

-0.329 (S)
-0.317 (S)
-0.290 (S)
-0.310 (S)
-0.334 (S)
-0.333 (S)
-0.330 (S)
-0.365 (A)
-0.346 (A)
-0.352 (A)

-0.329 (A)
-0.328 (A)
-0.330 (A)
-0.338 (A)
-0.347 (A)
-0.347 (A)
-0.348 (A)
-0.374 (S)
-0.350 (S)
-0.357 (S)

0.147 (A)
0.147 (A)
0.147 (A)
0.140 (A)
0.130 (A)
0.129 (S)
0.126 (S)
0.046 (S)
0.078 (S)
0.112 (S)

-0.920

-0.920

-0.264

LUMO + 1

E
(eV)

0.147 (S)
0.149 (S)
0.165 (S)
0.160 (S)
0.146 (S)
0.130 (A)
0.129 (A)
0.113 (A)
0.130 (A)
0.125 (A)

0.0
0.299
1.088
0.762
0.354
0.381
0.490
0.245
0.109
0.136

-0.264

SCHEME 4

FIGURE 8. Substituent effects on the energy of frontier molecular

orbitals of benzene.

Frontier MO energies found at the MP2(fc)/6-31G* level

confirm the role of HOMO-LUMO interactions in governing
substituent effects on eletrophilic aromatic nitration. Table 2
shows the energies of HOMO, HOMO - 1, LUMO and LUMO
+ 1 for several monosubstituted aromatic compounds. Interaction between an electrophile/oxidant such as NO2+ and the
aromatic compound should occur mainly in the positions
containing the highest HOMO coefficients. Actually, the
theoretical results indicate that the only minima found for
electron-donor substituents, which actually correspond to SET
intimate complex, are those where NO2+ is on the top of an
ipso or para position. This arrangement is what is seen for the
ipso and para complexes (Figure 9a and 9b). In contrast,
aromatics containing electron-withdrawing substituents form
complexes with NO2+ at the middle of the meta/ortho positions
(Figure 9c).

These HOMO-LUMO results together with the SET mechanism allow us to rationalize intriguing results in electrophilic
aromatic nitrations,27 such as the high degree of ipso substitution
such as for the reactions summarized in Scheme 4.
When the substituent is a good leaving group, a SET intimate
pair at the ipso position may be formed. Collapse of this
complex to the Wheland intermediate at the ipso position
followed by loss of the substituent affords the ipso substituted
product. This mechanism likely operates, for example, for the

FIGURE 9. Frontier orbital interactions within complexes 2a (a) and 2d (b), for X ) Cl, and 2c (c), for X ) NO2.
6200 J. Org. Chem., Vol. 71, No. 16, 2006

Electrophilic Aromatic Nitration

SCHEME 5

nitration of tert-butylbenzene and trimethylsilylbenzene (Scheme

4), which extensive nitration at the ipso position has been
observed.27 For monosubstituted aromatic compounds with
meta-orientating deactivated substituents (X)CN, NO2, CHO,
CF3), the SET to NO2+ is unfavorable. Therefore, the interaction
occurs between the HOMO of the aromatic compound and the
LUMO of NO2+. Since the HOMO of the aromatic compound
has higher density on the atoms that have higher MO coefficients, a complex should be formed with NO2+ placed above
the ortho and meta positions, as expected by MO analysis
(Figure 8). Actually, this qualitative analysis is reinforced by
our ab initio calculations. The evolution of the complex
(electron transfer is unfavorable) to the products involves the
formation of a complex (Wheland intermediate), which will
occur preferentially at the meta position, therefore minimizing
the repulsion between positive charges, as suggested by the
Ingold-Hughes mechanism.1 We therefore propose, for electrophilic nitration of aromatics, that ortho/para substituent
orientation, as well as the ipso substitution, is intimately related
to the SET mechanism, whereas the meta substituent orientation
is due to the Ingold-Hughes mechanism, given that SET cannot
operate (endothermic).
SET usually involves avoided crossings into the electronic
configurations (Figure 10). This avoided crossing happens at a
geometry where degenerescence of one or more electronic
configurations is necessary for correctly describing the electronic
state of the system.28 The geometry of the transition state for
SET is therefore given by the geometry that leads to the avoided
crossing in such systems. According to the Marcus theory, the
energy needed to distort the geometry from its equilibrium
position to the geometry where the configuration crossing occurs
is given by the reorganization energy ().29 For nitration, the
main electronic reorganization is due to the geometrical distortion of NO2+, once the aromatic compound presents little
geometric (nuclei) reorganization for SET.6,11 Considering the
(27) (a) Olah, G. A.; Malhotra, R.; Narang, S. C. Nitration Methods and
Mechanism; VCH: New York, 1989. (b) Perrin, C. L.; Skinner, G. A. J.
Am. Chem. Soc. 1971, 93, 3389. (c) Nightingale, D. V. Chem. ReV. 1947,
30, 117. (d) Moodie, R. B.; Schofield, K. Acc. Chem. Res. 1976, 9, 287.
(e) Attina`, M.; Cacace, F.; Ricci, A. J. Phys. Chem. 1996, 100, 4424.
(28) (a) Yarkony, D. R. J. Phys. Chem. 1996, 100, 18612-18628. (b)
Pross, A. Theoretical and Physical Principles of Organic ReactiVity;
Wiley: New York, 1995.
(29) (a) Marcus, R. A. AdV. Chem. Phys. 1999, 106, 1. (b) Marcus, R.
A. J. Electroanal. Chem. 2000, 483, 2.

HOMO and LUMO energies and considering that these energies

are good representations for the fundamental state, the analysis
of the frontier MO allows us to roughly identify the point where
SET occurs. This approach was successful for the analysis of
nitration of benzene.11
From the Marcus theory, the energy barrier for the electron
transfer (Ea) may be approximately given by the sum of the
reorganization energies of the aromatic compound (ArH+) and
that of the electrophile (NO2+). As commented above, the
reorganization energy of the aromatic compound is rather small
(ArH+ 0); therefore, this energy can be calculated by the
following equation:

E ) f(ArH+ + NO2+) f(NO2+)

The energy barriers for SET involving several substituted
benzenes can be estimated by looking for the ONO bond angle

FIGURE 10. Avoided crossing on the nitration of benzene and its

relation to the SET mechanism.

J. Org. Chem, Vol. 71, No. 16, 2006 6201

Queiroz et al.

FIGURE 12. Plot of the relative energy (kcal mol-1) of bent NO2+ in
relation to the linear form versus ONO bond angles.

FIGURE 11. Plot of the LUMO energies of NO2 versus ONO. The
arrows indicate the HOMO energies for the substituted C6H5X.

TABLE 3. Bending Angles of NO2+ Where Its LUMO Is

Isoenergetic to the HOMO of the Aromatic Substrate

substituent (X)

ONO
bond angle

bending energy
of NO2+
(kcal mol-1)

NO2
CF3
CHO
F, Cl
Br
H
CH3
OH
NH2

144
148
150
153
154
155
158
160
167

22.3
18.0
15.3
13.0
12.0
11.3
8.7
6.0
3.3

that affords the LUMO of NO2+ (Figure 11) isoenergetic to the

HOMO of the aromatic.11 MO analysis of NO2+ indicates that
its LUMO, initially a degenerate one, becomes lower in energy
as the ONO bond angle decreases, whereby resonance stabilization involving the nonbonded electron pairs on the oxygen atoms
decreases.11 For some ONO angles, the NO2+ LUMO should
become isoenergetic to the HOMO of the aromatic, therefore
making SET possible. We must know therefore the energy
needed to bend the NO2+ geometry to an angle where the
LUMONO2+ energy is equal to the HOMOArH energy. This
energy represents an upper limit for the activation energy, since
we are not considering the coupling of configurations, which
decreases the energy of the electronic state.28
Table 3 gives the energies needed to distort the NO2+
geometry so that its LUMO becomes isoenergetic to the HOMO
of the interacting aromatic compound ((NO2+)X). It may be
observed beforehand that as the aromatic compounds are more
activated for electrophilic aromatic substitution, their HOMO
energies become higher. Thus, SET also becomes more favored,
since the electronic reorganization energy in NO2+ necessary
to make its LUMO isoenergetic with these higher HOMO
energies is also smaller (Figure 11). For the more deactivated
aromatics, such as nitrobenzene, for SETto become operational,
the geometry of NO2+ should strongly change, resulting
6202 J. Org. Chem., Vol. 71, No. 16, 2006

FIGURE 13. Avoided crossings and its relation to the state formation;
high energy SET configuration.

thereafter in higher reorganization energy. As this reorganization

energy increases, SET becomes less favorable, thus the deactivated compounds will react according to the polar IngoldHughes mechanism.
The analysis of the reaction profile using the avoided crossing
model for electronic configurations and considering the SET
paradigm, allows us to predict successfully the observed
reactivity order for monosubstituted benzenes (Figure 12). SET
steps are favored by substituents which increases the energy
level of the HOMO of the aromatic. For higher energy HOMO
in the aromatics, the reorganization energy needed to lower the
energy of the LUMO of NO2+ (energy for bending the ONO
bond angle) should be correspondingly lower. This criterion
explains why electron-donating substituents such as CH3, OH,
and NH2 lead to activated aromatics with low activation energy,
the contrary being observed for electron-attracting substituents.
For a general analysis of the electrophilic aromatic substitution we need to estimate whether the SET configuration is
favored. Most probably, the mechanism of electrophilic aromatic
substitution may be represented by a continuum pathway, where
the SET and the Ingold-Hughes mechanisms are the extremes.
For systems with SET configurations of high energy (see Figure
13), we should expect the reaction to occur through the polar
Ingold-Hughes mechanism. However, if low energy SET
configurations are allowed (Figure 14), more intermediates are

Electrophilic Aromatic Nitration

FIGURE 14. Avoided crossings and its relation with the state
formation; low energy SET configuration, leading to the formation of
an SET intimate pair as an intermediate.

expected, and the process should proceed preferentially by the

SET pathway. For such situations, the intimate SET complex
(ArH+/NO2) may be intercepted.
Conclusions
On the basis of the present theoretical calculations and gasphase ion/molecule experiments, we propose an alternative and
detailed mechanistic scheme for electrophilic aromatic nitration.
This scheme consists of a continuum pathway in which the SET
and the classical polar Ingold-Hughes mechanism represent
extremes, and the prevalence of either one of these competing
mechanisms depends on whether the aromatic compound is
capable to transfer an electron to NO2+. The operating mechanism, SET or Ingold-Hughes, is proposed to govern regioselectivity of substituents. The ortho/para directing groups conduct
the reaction through the SET mechanism, while the meta
directing groups favor the classic polar Ingold-Hughes mechanism.
Experimental and Computational Details
The geometry of several species was optimized using standard
techniques, and, after geometry optimization, vibrational analysis
was performed. The resulting geometries were checked with respect
of being true minima on the potential energy surface, shown by
the absence of any imaginary frequencies. Calculations were
performed at B3LYP/6-311++G**//B3LYP/6-31++G** for all
structures. All differences in energy refer to enthalpy differences,
that is, zero-point energy and thermal expansion to 298 K
corrections are taken into account besides the electronic energy.
For frontier molecular orbital analysis, single point energy calculations at the MP2(fc)/6-31G*//B3LYP/6-31++G** level were
performed. All calculations were performed with the Gaussian 98
package of programs.30
The MS2 and MS3 experiments31 were performed using a
pentaquadrupole (QqQqQ) mass spectrometer.32 The QqQqQ

consists of three mass-analyzing quadrupoles (Q1, Q3, Q5), in

which ion mass-selection and mass-analysis are performed, and two
radio frequency-only reaction quadrupoles (q2, q4). Reactions were
then performed in q2 with selected aromatic compounds. For the
MS2 experiments, NO2+ of m/z 86 was generated by dissociative
70 eV electron ionization (EI) of nitromethane, whereas CH3NO2
NO2+ was generated by self-chemical ionization of nitromethane.
The reactant ion was then mass-selected by Q1, and after its ion/
molecule reactions in q2 with the neutral reagents, Q5 was used to
record the product ion mass spectrum, while operating Q3 and q4
in the full ion-transmission rf-only mode.
For the MS3 experiments, a product ion of interest was massselected in Q3 and dissociated in q4 by collisions with argon, while
Q5 was scanned across the desired m/z range to record the sequential
product triple stage (MS3) mass spectra. Nominal sample and neutral
gas pressures were typically 5 10-6 and 5 10-5 Torr,
respectively, as monitored by a single ionization gauge located
centrally in the vacuum chamber. The target gas pressure corresponds to a typical beam attenuation of 50-70%, viz., to multiple
collision conditions.33,34 However, lower reaction yields but similar
sets of products were always observed at lower pressure, mainly
single collision conditions in q2. Instrument parameters such as
quadrupole offset potentials and lens voltages were adjusted to
maximize the abundance of the ion/molecule reaction products. The
collision energies, calculated as the voltages difference between
the ions source and the collision quadrupole, were typically near 1
eV for ion-molecule reactions and 15 eV for CID.

Acknowledgment. Authors thank the Brazilian science

foundations CNPq, FINEP-MCT, FAPERJ, and FAPESP for
financial support.
Supporting Information Available: Tables containing total
energies, zero-point energies (ZPE), thermal corrections and Cartesian coordinates of the species 1-4 and other species of interest;
gas-phase IE for aromatic compounds and IE for their reactions
with NO2+; figures of the structures of interest containing selected
bond lengths at their optimized geometries. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0609475
(30) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry; Harper and Row: New York, 1987, p 52.
(31) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.7; Gaussian,
Inc.: Pittsburgh, PA, 1998.
(32) Eberlin, M. N. Mass Spectrom. ReV. 1997, 16, 113.
(33) Juliano, v. F.; Gozzo, F. C.; Eberlin, M. N.; Kascheres, C.; Lago,
C. L. Anal. Chem. 1996, 68, 1328.
(34) Sparrapan, R.; Mendes, M. A.; Carvalho, M.; Eberlin, M. N. Chem.s
Eur. J. 2000, 6, 321.

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